"Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options."
New guidelines issued jointly by the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) focus on men withadvanced stage disease and now include new treatments, including the use of PARP inhibitors in the metastatic castration-resistant (mCRCP) setting. The guidelines were co-presented by William T. Lowrance, MD, MPH, and Michael S. Cookson, MD, MMHC, during the 2020 American Urological Association Virtual Experience.1
“Men with advanced prostate cancer have exhausted local therapies and are now moving on to systemic options,” said Lowrance, who is an associate professor in the Division of Urology at the University of Utah School of Medicine and an investigator at the Huntsman Cancer Institute. “Specifically, these guidelines focus on men who experience biochemical recurrence, metastatic hormone-sensitive prostate cancer [mHSPC], non-metastatic castration-resistant prostate cancer [nmCRPC], or metastatic castration-resistant prostate cancer.”
The guidelines panel, made up of members from the 3 organizations, emphasized important principles in the early evaluation and counseling for these patients.
“In patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain a tissue diagnosis from the primary tumor or metastatic site,” Lowrance said. The guidelines recommend that counseling for patients with advanced prostate cancer should be based on the life expectancy, comorbidities, patient treatment preferences, and tumor characteristics. In addition, pain control and palliative care should be offered whenever possible.
In men who experience biochemical recurrence without metastatic disease, prostate-specific antigen (PSA) recurrence almost always precedes clinical detection of metastasis, Lowrance said. Therefore, clinicians should perform serial PSA measurements, clinical evaluation, and staging evaluations using standard-of-care imaging, including bone scans.
“Clinicians may use novel PET-CT scans in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging,” Lowrance said.
In this setting, a rising PSA after failure of local therapy and no metastatic disease demonstrated by conventional imaging, clinicians should offer observation or enrollment on to a clinical trial. Androgen deprivation therapy (ADT) should not be routinely initiated in this population. If ADT is initiated in the absence of metastatic disease, intermittent therapy may be offered in lieu of a continuous schedule.
In the setting of mHSPC, the guidelines recommend that patients receive genetic counseling and germline testing, regardless of age and family history. For treatment, the guidelines recommend that clinicians offer either chemotherapy (docetaxel) or continued ADT in combination with androgen pathway–directed therapy, including abiraterone plus prednisone, apalutamide (Erleada), or enzalutamide. The panel gave this treatment option a strong recommendation, with grade A evidence level data to support it. Another treatment option, but with a grade B evidence level, is to offer ADT with either luteinizing hormone–releasing hormone (LHRH) agonists or antagonists or surgical castration.
Evidence for these recommendations were based on findings from the CHAARTED (NCT00309985), STAMPEDE (NCT00268476), LATITUDE (NCT01715285), TITAN (NCT02489318), ARCHES (NCT02677896), and ENZAMET (NCT02446405) studies (TABLE).3-8
Recommendations in the Non-Metastatic Setting
Until recently, there were no agents available to treat men with nmCRPC, said Cookson, professor and chairman of the Department of Urology at the University of Oklahoma College of Medicine in Oklahoma City. Based on a new end point, metastases-free survival (MFS), 3 new androgen receptor antagonists—apalutamide, enzalutamide, darolutamide (Nubeqa)—have gained FDA approval based on phase 3 clinical trials SPARTAN (NCT01946204), PROSPER (NCT02003924), and ARAMIS (NCT02200614), respectively.9-11
“Importantly, all men in this nonmetastatic CRPC group were at high risk for developing metastatic disease, with PSA doubling times of less than 10 months,” Cookson said. He also noted that the PROSPER study, whose survival data was subsequently published after the guidelines were finalized, demonstrated the benefit of enzalutamide in nmCRPC, with an overall survival of 67 months and a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.61-0.89; P = .001).12
PARP Inhibitor Recommendation
In the mCRPC setting, the use of a PARP inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) who have a deleterious or suspected deleterious germline or somatic homologous recombination repair mutation following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), and/or a taxane-based chemotherapy (docetaxel) is now recommended. The recommendation has the potential to benefit nearly 20% of patients with mCRPC. It is estimated that 23% of these prostate cancer tumors harbor alterations to DNA damage response and repair (DDR) genes, with 8% having DDR germline mutations.13
In the mCRPC setting, Cookson noted that DNA repair gene alterations are common and that among DDR alterations, BRCA2 genes were the most frequently altered (12.7%).
Cookson spoke about data from the phase 3 PROfound trial that looked at men with mCRPC and homologous recombination repair mutations who had previously failed enzalutamide, abiraterone, or docetaxel-based chemotherapy.. Enzalutamide, abiraterone, or docetaxel-based chemotherapy had failed in these patients.13 The investigators observed a median PFS of 7.4 months in those who were treated with olaparib (Lynparza) versus 3.6 months for the control of physician’s choice or enzalutamide or abiraterone. Results from the trial led to the approval of olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.14 Cookson said rucaparib (Rubraca) is also approved following ADT and chemotherapy.15
In patients who cannot use a PARP inhibitor, platinum-based chemotherapy may be offered, according to the guidelines. Further, in patients with mCRPC whose tumors have mismatch repair–deficient or microsatellite instability–high status, clinicians should offer pembrolizumab (Keytruda).
These guidelines are a welcome addition as prostate cancer is the most commonly diagnosed solid tumor malignancy in men in the United States and remains the second leading cause of cancer deaths for this population, said Lowrance.
1. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline. Accessed June 26, 2020. https://www.auanet.org/guidelines/advanced-prostate-cancer
2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657
3. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5
4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174
5. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
6. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799
7. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835
8. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. February 14, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-non-metastatic-castration-resistant-prostate-cancer
9. FDA approves enzalutamide for castration-resistant prostate cancer. News release. FDA. July 13, 2018. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-castration-resistant-prostate-cancer
10.FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed June 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer
11. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892
12. Zhang W, van Gent DC, Incrocci L, van Weerden WM, Nonnekens J. Role of the DNA damage response in prostate cancer formation, progression and treatment [published correction appears in Prostate Cancer Prostatic Dis. 2019 Jul 17;:]. Prostate Cancer Prostatic Dis. 2020;23(1):24-37. doi:10.1038/s41391-019-0153-2
13. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
14. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 19, 2020. Accessed June 28, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer
15. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 15, 2020. Accessed June 28, 2020. https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate